The present invention relates to a device and method for determining viscosity of a liquid sample by capacitance or resistance, and, in particular, to a device and method for analyzing clotting of a blood specimen by a patient in a home testing environment, substantially without the need for intervention by highly trained clinical laboratory technicians or other technical medical personnel.
Clotting time is the amount of time required for a blood sample from a patient to clot. The determination of clotting time is important for patients who are receiving anti-coagulant therapy, such as those patients taking the drug warfarin, for example. The dosing regimen for such drugs must be determined for each individual patient, and then adjusted according to the clotting time. A dosing regimen which does not increase clotting time in one patient might result in an excessively and dangerously prolonged clotting time in another patient. The determination of dosing regimen is further complicated by the pharmacological properties of some anti-coagulant drugs, such as warfarin, which may remain highly bound to proteins in the blood, so that the amount of bioavailable drug in the body may be difficult to adjust. Thus, clotting time must be carefully monitored for each patient.
Unfortunately, currently clotting time can only be measured in a clinical laboratory setting by a clinical laboratory technician. The devices employed for the measurement of clotting time in the laboratory require the time period for clotting to be determined by optical or mechanical analysis of the blood sample. For example, a commercially available mechanical diagnostic assay is available from Boehringer Mannheim Corp and is based on the automated analysis of the behavior of metal balls which are stirred inside the plasma specimen by a magnet. These balls are examined with automated machine vision techniques to determine when the balls no longer move under the influence of the magnetic force. Clotting is assumed to have occurred when such lack of movement within the sample is observed. According to other disclosed diagnostic assays in the prior art, the blood sample to be analyzed is placed in a capillary. When the sample no longer moves through the capillary, clotting has occurred. The determination of the cessation of movement through the capillary is done by optical analysis. Optical analysis may be performed manually through observation of the sample within the capillary by a trained laboratory technician, or automatically by determining changes in the optical density of the blood sample with a light source and a photodetector.
For example, an optical device for manual visual detection of clotting has been disclosed in U.S. Pat. No. 3,951,606. A similar, disposable device has been disclosed in PCT Application No. WO 96/00395. More automated devices, in which changes in optical density are measured by sending a beam of light through the sample and detecting the amount of light which passes through the sample by a photodetector, are disclosed in U.S. Pat. No. 5,039,617 and U.S. Pat. No. 5,197,017. All of these devices suffer from the drawback of being either complex to operate or complex to construct. For example, measurement of clotting time by visual inspection of a blood sample as it moves through a capillary requires intense concentration in order to accurately determine the moment when the sample stops moving. Such concentration may not be difficult for a trained laboratory technician, but places an excessive burden on the lay patient who wishes to measure clotting time in a home testing environment. Thus, although at least one disposable version of a device for determination of clotting time by visual analysis has been disclosed in PCT Application No. WO 96/00395, as yet no such device is available for the home testing market.
The alternative form for optical analysis, in which a beam of light is transmitted from a light source through the blood sample to a photodetector, suffers from the drawback of being too complex and expensive to manufacture as a home testing device. Such a device would also require careful maintenance and calibration on a regular basis, which also places an excessive burden on the lay patient for home testing. Thus, automated optical analysis is not suitable for the home testing environment.
Devices for the electrical determination of blood clotting have also been disclosed. For example, one such device determined clotting of a blood sample by measuring changes in the electrical impedance of the sample (A. Ur, Nature, 226:269–270, 1970 and U.S. Pat. No. 3,699,437). A similar device was also disclosed in U.S. Pat. No. 3,674,012. However, this device required complex, delicate and sensitive laboratory equipment to measure the impedance of the sample, which would not be suitable for home testing. Furthermore, although the device was first disclosed more than twenty years ago, no commercially available equivalent device has been produced for the laboratory or for the home testing environment, an indication of the technical difficulties inherent in the design, production and operation of such a device. Thus, the measurement of electrical impedance is not suitable for the determination of clotting time in the home testing environment.
Other devices employing some type of electrical measurement of clotting time have been disclosed, but again none of these devices is suitable for the home testing environment. For example, U.S. Pat. No. 5,491,408 discloses a device which determines changes in viscosity of a liquid sample by measuring variations in voltage as the sample is agitated by a vibration generator. Clearly, such a device would be sensitive to vibrations in the environment and would therefore not be suitable for operation by a lay patient.
DDR (former East German) Patent No. DD 237454 discloses an apparatus for determining blood coagulation time. One electrode is dipped at intervals into a blood sample held in a metal block thermostat and then raised, and the capacitance between the raised electrode and the metal block is measured. As the blood coagulates, a filament of viscous liquid is attached to the raised electrode, changing the capacitance. This apparatus would certainly not be suitable for operation by a lay patient, since it requires careful manipulation of the equipment and manual monitoring of the progress of coagulation. Furthermore, the disclosed apparatus could not easily be automated in a small portable device. Thus, the apparatus disclosed in DDR Patent No. DD 237454 would certainly not be suitable for the home testing environment.
As another example, U.S. Pat. No. 5,601,995 discloses a device for detecting blood clotting. This device includes a porous sheet for receiving the blood sample. Clotting is then detected either optically or electrically, by the measurement of resistance. However, the porous sheet has a number of drawbacks as a receptacle for the blood sample. For example, various substances such as gelatin coating, surfactants or hydrophilic polymers are added to the sheet in order to overcome such problems as controlling the speed of transport through the porous medium and/or to promote adhesion of the fibrin clots (column 5, lines 16–34). In addition, since the blood (or any liquid specimen) moves inside the porous sheet, contact of the liquid with the electrodes, which touch the surface of the sheet, may not be sufficiently intimate to provide an accurate measurement of the electrical properties of the liquid specimen. Thus, the device disclosed in U.S. Pat. No. 5,601,995 is clearly deficient.
As yet another example, both U.S. Pat. No. 3,840,806 and PCT Application No. WO 94/16095 disclose devices which both measure electrical resistance and optical density of a sample. As noted previously, the measurement of optical density requires excessively complex equipment for the home testing environment. Furthermore, although over twenty years have passed since U.S. Pat. No. 3,840,806 was publicly disclosed, and four years have passed since PCT Application No. WO 94/16095 was publicly disclosed, no such device has been made available for the home testing environment, nor has any announcement been made of any clinical trials for such a device. Thus, clearly these prior art electrical devices have not proven to be suitable for operation by the lay patient.
One example of a device which has been successfully used by the lay patient in the home testing environment can be found in an entirely different medical area. Diabetics now use a small, highly portable electrical device for the determination of blood glucose levels. The operation of this device is quite simple. A drop of blood is taken from the patient and placed on a small card which is inserted into the device. After a brief period of time, the concentration of glucose in the sample is displayed on a small screen. Thus, commercially available glucose testing devices are simple to operate by the lay patient and are sufficiently robust to withstand the rigors of the home testing environment, yet are sufficiently accurate to generate clinically significant results.
Clearly, an equivalent device for the determination of clotting time in the home environment by the lay patient would be highly useful and commercially successful. Home testing of clotting time offers a number of advantages, including greater clinical utility of measurement through daily assessments rather than by a weekly or bi-weekly measurement at a clinic, and greater convenience for the lay patient, enabling the patient to immediately seek medical attention in response to any sudden changes in the measured clotting time. Currently, patients must travel to a clinic, have a blood sample withdrawn by a healthcare professional, and then wait for the results. Such a complicated, inconvenient and time-consuming process can potentially result in reduced patient compliance. By contrast, testing in the home is potentially both more convenient and less expensive, and may also result in increased patient compliance. Unfortunately, such a home testing device for the measurement of clotting time is simply not available. Thus, lay patients cannot currently measure clotting time in the home, but must instead resort to the less desirable process of clinical testing.
There is therefore a need for, and it would be useful to have, a method and a device for the measurement of clotting time which can be performed by the lay patient in the home testing environment, which would be both robust and accurate, which would also be simple to operate and which could potentially be employed to determine the viscosity of other types of liquid samples, preferably through the measurement of electrical capacitance, and which is substantially automated for relatively minimal intervention by a lay patient.